This shared instrumentation proposal seeks funding for the purchase of a Thermo Scientific? Orbitrap Fusion Lumos? ETD with FAIMS Pro mass spectrometer system. This platform will be integrated with a nano- electrospray ionization source, an on-line nano-capillary LC system Ultimate 3000, and an automated sample injector. All costs will be accounted for with this proposal. We propose to operate this integrated Orbitrap Lumos mass spectrometry system exclusively for high-throughput on-line separation and analysis of complex peptide and protein mixtures as part of large group of 12 independent principal investigators from the Buck Institute and five external investigators who represent a total of five institutions or universities. Together, these researchers bring together 19 NIH-funded grants and one R01 supplement, all of which have significant needs for state-of-the-art mass spectrometry for various proteomics applications that require the highest resolution, sensitivity, dynamic range and capability for efficient multiplexing. The most critical features of this new instrumentation will be to the ultra-high resolution of data acquisition in MS1 (500,000 at m/z 200) with up to 1 million resolution (in the 1M option), exquisite mass accuracy, and many different isobaric chemical labeling (TMT) quantification strategies. We will also implement ion mobility features (FAIMS) for additional gas phase separation. Overall, this highly integrated platform combining quadrupole, linear ion trap, and Orbitrap mass analyzers and featuring CID, HCD, ETD and EThcD, and UVPD fragmentation techniques offers unforeseen versatility in different scan-types and mass spectrometric workflows possible. Data-dependent and data- independent acquisitions allow for in-depth proteome coverage and many proteomic quantification workflows. Overall, the acquisition of this instrument to the Mass Spectrometry Core at the Buck Institute for Research on Aging will greatly improve the throughput, experimental design, and discovery rate of our 17 proposed projects that are examining key issues of human health and health span, including the biology of aging, neuro- degenerative disease, diabetes, cancer, and disease biomarker discovery.